The present invention relates to methods for predicting clinically significant prostate cancer in a biopsy using a urine sample of an individual suspected of suffering from prostate cancer. It is based on expression analysis of normalised prostate tumour markers. The present methods are especially suitable for predicting prostate cancer with a Gleason score of seven or more in individuals with a serum prostate-specific antigen (sPSA) level lower than 15 ng/ml. The present invention further relates to kits of parts for predicting clinically significant prostate cancer in a urine sample based on expression analysis and to the use of normalised prostate tumour markers for detecting prostate cancer in a urine sample.
Worldwide, prostate cancer or PCa is the second most frequently diagnosed cancer among men, with 1.1 million estimated new cases and 307.500 estimated deaths in 2012. Since the introduction of serum prostate-specific antigen (sPSA) testing, the incidence of PCa has increased. However, sPSA-testing has also led to an increased amount of unnecessary biopsies and diagnosis of clinically insignificant tumors which would not have been life-threatening (potential overtreatment); especially in the sPSA ‘grey-zone’ (4.0-10.0 ng/ml) where 65-70% of men have a negative biopsy result. Men with indolent disease, who undergo treatment, may suffer complications without a reduction in their risk of dying from PCa. Generally, men with high-grade PCa have a high probability of dying from PCa within 10 years, whereas men with low-grade PCa have a minimal risk of dying from this disease.
The major challenge is to improve the detection of clinically significant or high-grade PCa in an early stage. Both overdiagnosis and overtreatment could be reduced if PCa-specific biomarkers could distinguish indolent from aggressive tumors. Ideally the biomarkers could be measured in a sample that can be obtained non-invasively, for example in urine.
The Prostate CAncer gene 3 (PCA3)-based urinary test (Progensa® PCA3, GenProbe) is the only FDA-approved molecular diagnostic test for the detection of PCa in urine. PCA3 was identified as a gene encoding a long non-coding RNA that was consistently upregulated in PCa. PCA3 was shown to be of value in PCa detection, however, the relation with tumor aggressiveness and thus prognostic value remains controversial.
A stepwise approach for the identification and selection of new biomarkers using gene expression profiling has been suggested. A gene panel measured in urinary sediments predicted Gleason score ≥7 upon prostate biopsy. The test, based on mRNA levels of Homeobox C6 (HOXC6), Distal-less Homeobox 1 (DLX1), and Tudor domain containing 1 (TDRD1), was shown to have independent additional value to sPSA for predicting high-grade PCa upon biopsy. The combination of HOXC6, DLX1, and TDRD1 outperformed Progensa® PCA3. Furthermore, the predictive accuracy could be improved when urinary HOXC6, DLX1, and TDRD1 were combined with sPSA. HOXC6, DLX1, and TDRD1 are upregulated in PCa and these genes may be involved in the onset of PCa and are associated with high-grade PCa. However, although the test showed promising results when performed on a urine sediment sample, analysis of whole urine samples were not satisfactory.